CONICET | Buscador de Institutos y Recursos Humanos

Muscarinic cholinergic modulation of neurotransmission in rat hippocampus has been recurrently documented in several works, though the involvement of the different receptor subtypes has not been completely characterized. Muscarinic toxins (MTs) 1 and 2 from Dendroaspis angusticeps snake venom act as selective M1 receptor agonists and M4 antagonists. MT2 has 4-fold higher affinity for M1 than for M4 receptor. Both toxins enhanced field potentials (fEPSP) at CA1 synapses in rat hippocampal fresh slices. This MT2 enhancement of fEPSP was effectively blocked by both atropine (specific though non-selective muscarinic antagonist) and pirenzepine (selective antagonist for M1 and M4 receptors), strongly suggesting M1 receptor involvement in the phenomenon. Furthermore, scopolamine (specific non-selective antagonist) and pirenzepine blocked LTP induction by theta burst stimulation (TBS-LTP) in the same synapses.We used MT7, the most selective M1 antagonist known, to elucidate if the effect of MT1 and MT2 on fEPSP recorded at CA1 synapses was mediated through M1 receptor subtype and if the blockade of this receptor by classical muscarinic antagonists was directly responsible for TBS-LTP inhibition. MT7 (10 nM) completely abolished MT1 and MT2-induced increases in fEPSP and TBS-LTP induction.Taking into account that both MT1 and MT2 have significant affinities for α-adrenergic receptors, we also performed radioligand binding assays in rat hippocampal synaptosomal membranes to evaluate MT7 inhibition of both 3H-N-methylscopolamine (3H-NMS, muscarinic ligand) and 3H-prazosin (3H-PRZ, α-adrenergic ligand) binding. MT7 inhibited 3H-NMS binding but did not inhibit 3H-PRZ binding. Moreover, maximal inhibition of 3H-NMS binding was 38 ± 5%, close to M1 ratio in rat hippocampus.Altogether these results demonstrate that M1 muscarinic receptors positively modulate basal transmission and that they are required for LTP induction by TBS at CA1 synapses.